Chotosan ameliorates cognitive and emotional deficits in an animal model of type 2 diabetes: possible involvement of cholinergic and VEGF/PDGF mechanisms in the brain

Abstract

BackgroundDiabetes is one of the risk factors for cognitive deficits such as Alzheimer’s disease. To obtain a better understanding of the anti-dementia effect of chotosan (CTS), a Kampo formula, we investigated its effects on cognitive and emotional deficits of type 2 diabetic db/db mice and putative mechanism(s) underlying the effects.MethodsSeven-week-old db/db mice received daily administration of CTS (375 – 750 mg/kg, p.o.) and the reference drug tacrine (THA: 2.5 mg/kg, i.p.) during an experimental period of 7 weeks. From the age of 9-week-old, the animals underwent the novel object recognition test, the modified Y-maze test, and the water maze test to elucidate cognitive performance and the elevated plus maze test to elucidate anxiety-related behavior. After completing behavioral studies, Western blotting and immunohistochemical studies were conducted.ResultsCompared with age-matched non-diabetic control strain (m/m) mice, db/db mice exhibited impaired cognitive performance and an increased level of anxiety. CTS ameliorated cognitive and emotional deficits of db/db mice, whereas THA improved only cognitive performance. The phosphorylated levels of Akt and PKCα in the hippocampus were significantly lower and higher, respectively, in db/db mice than in m/m mice. Expression levels of the hippocampal cholinergic marker proteins and the number of the septal cholinergic neurons were also reduced in db/db mice compared with those in m/m mice. Moreover, the db/db mice had significantly reduced levels of vasculogenesis/angiogenesis factors, vascular endothelial growth factor (VEGF), VEGF receptor type 2, platelet-derived growth factor-B, and PDGF receptor β, in the hippocampus. CTS and THA treatment reversed these neurochemical and histological alterations caused by diabetes.ConclusionThese results suggest that CTS ameliorates diabetes-induced cognitive deficits by protecting central cholinergic and VEGF/PDGF systems via Akt signaling pathway and that CTS exhibits the anxiolytic effect via neuronal mechanism(s) independent of cholinergic or VEGF/PDGF systems in db/db mice.

Butea superba–Induced Amelioration of Cognitive and Emotional Deficits in Olfactory Bulbectomized Mice and Putative Mechanisms Underlying Its Actions

“…OBX-induced decrease in the expression level of ChAT and its reversal by tacrine are indeed consistent with our previous reports (8,10). Daily tacrine administrationinduced protection of septal cholinergic neurons has also been observed in an animal model of type 2 diabetes, the cognitive dysfunction of which was ameliorated by tacrine (23,37,38), suggesting that elevation of endogenous acetylcholine protects cholinergic neuron from degeneration under pathological conditions. Interestingly, in this study, we found that systemic administration of BS, as well as of tacrine, inhibited the ex vivo activity of AChE in brain tissue.…”

Kampo Formulations, Chotosan, and Yokukansan, for Dementia Therapy: Existing Clinical and Preclinical Evidence

“…as well as tacrine (2.5 mg/kg, i.p.) ameliorated the cognitive deficit of db/db mice without affecting their motor activity, serum glucose level, or body weight (28), leading to the concept that the ameliorative effect of CTS on diabetes-induced cognitive deficits involves a mechanism independent of anti-hyperglycemia or anti-obesity (28). This was supported by our recent findings that CTS administration ameliorated cognitive deficits but not serum glucose abnormality in streptozotocin-treated rats of a type 1 diabetes model (unpublished data).…”

“…This was supported by our recent findings that CTS administration ameliorated cognitive deficits but not serum glucose abnormality in streptozotocin-treated rats of a type 1 diabetes model (unpublished data). Moreover, it is interesting that CTS as well as the anxiolytic drug diazepam improved anxiety-like behavior observed in db/db mice (28). This apparent anxiolytic-like effect of CTS is in contrast to its effect on a reduced level of anxiety-like behavior observed in an animal model of aging, SAMP8.…”

“…Recent reports from our laboratory (27,28) and others (29) have demonstrated that C57BLKS/J-db/db mice, an animal model of type 2 diabetes, show impaired cognitive behavior, anxietylike behavior, and reduced motor activity at the age of 9 weeks and older compared with their age-matched non-diabetic m/m littermates. Interestingly, when started on daily administration of drugs at the age of 7 weeks, CTS (375 -750 mg/kg, p.o.)…”

“…However, the neuronal mechanisms underlying the contradictory effects of CTS on anxiety-related behavior in SAMP8 and db/db mice are unclear. Nonetheless, since the acetylcholinesterase inhibitor tacrine, a prototype anti-AD drug, has no effect on anxiety-related behavior in these animal models (28), the potential of CTS to improve both cognitive and emotional deficits should be beneficial for the treatment of dementia patients.…”